The following description is provided to assist the understanding of the reader. None of the information provided or references cited are admitted to be prior art to the present invention.
Cholesterol is a lipid that plays a key role in the biology of mammalian cells. It helps to build and maintain the integrity of cell membranes, serves as a precursor for the synthesis of vitamin D and of the various steroid hormones, plays a role in cell signaling processes, and aids in the manufacture of bile and in the metabolism of fat soluble vitamins. Because cholesterol is insoluble in water, the body makes lipoproteins to help the extracellular transport of cholesterol in the circulatory system. Low-density lipoproteins (“LDL”) carry cholesterol from the liver to body tissues which need it. High density lipoproteins (“HDL”) pick up cholesterol in the blood stream and carry it back to the liver where it is converted into bile and used for digestion. Cholesterol being carried to the body tissues by low-density lipoproteins is taken up by cells via LDL receptor-mediated endocytosis so that it can be used in its various capacities.
A complex set of homeostatic mechanisms maintains strict control over the level of cholesterol within the cell. Although it is known that intracellular cholesterol levels are regulated through a complex set of transcriptional and post-transcriptional feedback mechanisms, intracellular sterol transport is generally a poorly understood cellular process. It is known, however, that the endoplasmic reticulum is the site of the late steps of cholesterol biosynthesis and of all of the cholesterol homeostatic mechanisms including activation of transcriptional regulation of sterol-regulated genes through SREBP, the regulated degradation of HMG-CoA-reductase, and storage of excess cholesterol in the form of cholesteryl esters. Consequently, the specific delivery of sterols to the endoplasmic reticulum is required for cholesterol biosynthesis and normal cholesterol homeostasis.
Defects in the mechanisms of cellular cholesterol homeostasis can lead to developmental and/or neurodegenerative disorders as well increased levels of circulating LDL and an increased risk of coronary heart disease. Coronary heart disease is caused by atherosclerosis, or a buildup of plaque, in the walls of the coronary arteries. Plaque is composed of cholesterol and other fatty materials. As the deposits slowly narrow the coronary arteries, the heart receives less blood. Eventually, diminished blood flow may cause angina pectoris or myocardial infarction. Angina pectoris is chest pain or discomfort that occurs when an insufficient amount of enough oxygen-rich blood is flowing to an area of the heart muscle. This causes pressure and pain in the chest, shoulders, arms, neck, back, and jaw. Myocardial infarction, commonly known as a heart attack, occurs when blood flow to an area of the heart muscle is completely blocked. This prevents oxygen-rich blood from reaching that area of the heart muscle, subsequently causing it to die. Without immediate treatment, myocardial infarction can lead to serious problems and even death.
Because improper regulation of cholesterol homeostasis can lead to serious health problems, there remains a need for a better understanding of the intracellular cholesterol transport mechanisms which will allow for more appropriate and accurate diagnosis and treatment.